
The genes IDH1 and IDH2 demonstrate significant associations with all three layers for the FLAIR sequence. Several recent studies [1]}, [2]}, [3]} have highlighted the prognostic importance of IDH mutations in gliomas as well as their distinctive genetic and clinical characteristics. Mutations that affect IDH1 were identified in more than 70% of low grade gliomas and in glioblastomas that developed from lower-grade lesions; most of the other tumors often had mutations affecting the gene IDH2 [1]}. These mutations were also shown to be strong predictors for survival, specifically in the case of LGG [2]}. During the developmental stage of most LGG tumors, one of the earliest genetic events is the acquisition of IDH1 or IDH2 mutation [3]}.

The PI3K pathway (group of genes), which includes genes such as PTEN, PIK3CA and PIK3R1, is one of the most deregulated and druggable pathways in human cancer [7]}. We see associations of the genes PTEN, PIK3CA and PIK3R1 with the spherical shells in both T2 and FLAIR. The PI3K pathway controls multiple cellular processes including metabolism, motility, proliferation, growth and survival [8]}. Somatic mutations in PIK3R1 act as oncogenic driver events in gliomas and are known to increase signaling through the PI3K pathway; they also promote tumorigenesis of primary normal human astrocytes in an orthotopic xenograft model [9]}.

Another significant association across all of the three spherical shells in the FLAIR imaging sequence, and partially in T2, is with the genes ARID1A and ARID2. Studies have shown that somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types [10]}. ARID1A is known to be a tumor suppressor and inhibits glioma cell proliferation via the PI3K pathway [11]}. ARID2 is a gene associated with chromatin organization and has been predicted to be a glioma driver [12]}. Moreover, recent studies have identified ARID2 as a direct target and functional effector in other cancers such as oral cancer [13]}.

The genes PTPN11 and NIBPL also present significant associations across all three spherical shells in the FLAIR sequence. Additionally, NIPBL presents association across all spherical shells in T2. NIPBL is a somatically altered glioma gene that is known to be a crucial adherin subunit, and is essential for loading cohesins on chromatin [12]}. PTPN11 is known to mediate gliomagenesis in both mice and humans [15]}.

NRAS is a member of the RAS oncogene family, which encodes small enzymes involved in cellular signal transduction [16]}. In our analysis, NRAS shows significant association with the exterior layers of the tumor in FLAIR. RAS pathways, when activated, trigger downstream signaling pathways such as MAPKs and PI3K/AKT, which modulate cell growth and survival [17]}. NRAS was also identified as a gene which promoted oncogenesis in glioma stem cell [18]}.

We see significant associations of the gene CIC with the inner and middle layers in T1, T1Gd and T2. CIC is a transcriptional repressor that counteracts activation of genes downstream of receptor tyrosine kinase (RTK)/RAS/ERK signaling pathways [19]}. Loss of CIC potentiated the formation and reduced the latency in tumor development in an orthotopic mouse model of glioma [20]}. Tumorigenesis in high-grade gliomas is attributed to hyperactive RTK/RAS/ERK signaling, while CIC has a tumor suppressive function [19]}. This indicates an inverse functional relationship between CIC and the genes in RTK/RAS/ERK pathways (e.g., NRAS). Interestingly, we see that associations with CIC are picked only when there are no significant associations with NRAS.

